Rapid dissolution formulation of a calcium receptor-active compound

ABSTRACT

The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a calcium receptor-active compound and at least one pharmaceutically acceptable excipient, wherein the composition has a controlled dissolution profile. The present invention further relates to a method of manufacturing the pharmaceutical composition, as well as a method of treating a disease using the pharmaceutical composition.

This application claims the benefit of priority of U.S. ProvisionalPatent Application No. 60/502,219, filed Sep. 12, 2003.

Calcium receptor-active compounds are known in the art. One example of acalcium receptor-active compound is cinacalcet HCl, which is described,for example, in U.S. Pat. No. 6,001,884. Such calcium receptor-activecompounds may be insoluble or sparingly soluble in water, particularlyin their non-ionized state. For example, cinacalcet has a solubility inwater of less than about 1 μg/mL at neutral pH. The solubility ofcinacalcet can reach about 1.6 mg/mL when the pH ranges from about 3 toabout 5. However, when the pH is about 1, the solubility decreases toabout 0.1 mg/mL. Such limited solubility can reduce the number offormulation and delivery options available for these calciumreceptor-active compounds. Limited water solubility can also result inlow bioavailability of the compounds.

There is therefore a need to maximize the dissolution of the calciumreceptor-active compound from a dosage form, and potentially during invivo exposure. There is also a need to improve the bioavailability ofthe calcium receptor-active compound during in vivo exposure.

One aspect of the present invention provides a pharmaceuticalcomposition comprising at least one calcium receptor active compound incombination with at least one pharmaceutically acceptable carrier.Certain embodiments of the present invention are directed to apharmaceutical composition with a defined dissolution profile.

The invention also provides a method of manufacturing the pharmaceuticalcomposition to achieve the desired dissolution profile, as well as amethod of treating a disease using the pharmaceutical composition. Inaddition, certain embodiments of the present invention are directed to amethod for controlling dissolution rate of a formulation comprising thepharmaceutical composition.

According to one aspect of the invention, the invention provides apharmaceutical composition comprising an effective dosage amount of atleast one calcium receptor-active compound and at least onepharmaceutically acceptable excipient, wherein the composition has adissolution profile in 0.05 N HCl, measured according to a dissolutiontest conducted in United States Pharmacopeia (USP)—National Formulary(NF) (USP 26/NF 21), chapter 711 using a USP 2 apparatus at atemperature of 37° C.±0.5° C., and at a rotation speed of 75 r.p.m.,which comprises from about 50% to about 125% of a target amount of thecalcium receptor-active compound being released from the composition nolater than about 30 minutes from the start of the test.

According to another aspect of the invention, the invention provides apharmaceutical composition comprising an effective dosage amount of atleast one calcium receptor-active compound and at least onepharmaceutically acceptable excipient, wherein the composition has adissolution profile in 0.05 N HCl, measured according to a dissolutiontest conducted in USP 26/NF 21, chapter 711 using a USP 2 apparatus at atemperature of about 37° C., and at a rotation speed of about 75 r.p.m.,which comprises from about 50% to about 125% of a target amount of thecalcium receptor-active compound being released from the composition nolater than about 30 minutes from the start of the test.

The invention also provides a method of controlling the dissolution rateof a formulation comprising an effective dosage amount of a calciumreceptor-active compound and at least one pharmaceutically acceptableexcipient, the method comprising producing the formulation in agranulator which has a volume ranging from about 1 L to about 2000 L,and contains water in a granulation level ranging from about 10% toabout 50% relative to the weight of the dry powders in the granulator.

The calcium receptor-active compound useful in the claimed invention maybe a calcimimetic compound or a calcilytic compound. As used herein, theterm “calcimimetic compounds” refers to compounds that bind to a calciumreceptor, and induce a conformational change that reduces the thresholdfor calcium receptor activation by the endogenous ligand Ca²⁺, therebyreducing parathyroid hormone (“PTH”) secretion. These calcimimeticcompounds can also be considered allosteric modulators of the calciumreceptor. As used herein, the term “calcilytic compounds” refers tocompounds that act as calcium receptor antagonists, and stimulate PTHsecretion.

The calcimimetic compounds and calcilytic compounds useful in thepresent invention include those disclosed in, for example, EuropeanPatent No. 933 354; International Publication Nos. WO 01/34562, WO93/04373, WO 94/18959, WO 95/11221, WO 96/12697, WO 97/41090; U.S. Pat.Nos. 5,981,599, 6,001,884, 6,011,068, 6,031,003, 6,172,091, 6,211,244,6,313,146, 6,342,532, 6,363,231, 6,432,656, and U.S. Patent ApplicationPublication No. 2002/0107406. The calcimimetic compounds and/orcalcilytic compounds disclosed in these patents and publishedapplications are incorporated herein by reference.

In certain embodiments, the calcium receptor-active compounds are chosenfrom compounds of formula (I) and pharmaceutically acceptable saltsthereof

wherein:

X₁ and X₂, which may be identical or different, are each a radicalchosen from CH₃, CH₃O, CH₃CH₂O, Br, Cl, F, CF₃, CHF₂, CH₂F, CF₃O, CH₃S,OH, CH₂OH, CONH₂, CN, NO₂, CH₃CH₂, propyl, isopropyl, butyl, isobutyl,t-butyl, acetoxy, and acetyl radicals, or two of X₁ may together form anentity chosen from fused cycloaliphatic rings, fused aromatic rings, anda methylene dioxy radical, or two of X₂ may together form an entitychosen from fused cycloaliphatic rings, fused aromatic rings, and amethylene dioxy radical; provided that X₂ is not a 3-t-butyl radical;

n ranges from 0 to 5;

m ranges from 1 to 5; and

the alkyl radical is chosen from C1-C3 alkyl radicals, which areoptionally substituted with at least one group chosen from saturated andunsaturated, linear, branched, and cyclic C1-C9 alkyl groups,dihydroindolyl and thiodihydroindolyl groups, and 2-, 3-, and4-piperid(in)yl groups; and the stereoisomers thereof.

Calcium receptor-active compounds useful in the present invention can beused in the form of pharmaceutically acceptable salts derived frominorganic or organic acids. The salts include, but are not limited to,the following: acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate, mandelate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate, mesylate, and undecanoate. When compounds of the inventioninclude an acidic function such as a carboxy group, then suitablepharmaceutically acceptable salts for the carboxy group are well knownto those skilled in the art and include, for example, alkaline, alkalineearth, ammonium, quaternary ammonium cations and the like. Foradditional examples of “pharmacologically acceptable salts,” see infraand Berge et al., J. Pharm. Sci. 66:1 (1977). In certain embodiments ofthe invention salts of hydrochloride and salts of methanesulfonic acidcan be used.

In some embodiments of the present invention, the calcium-receptoractive compound can be chosen from cinacalcet, i.e.,N-(1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane,cinacalcet HCl, and cinacalcet methanesulfonate. The cinacalcet HCl andcinacalcet methanesulfonate can be in various forms, such as amorphouspowders, crystalline powders, and mixtures thereof. For example, thecrystalline powders can be in forms including polymorphs,psuedopolymorphs, crystal habits, micromeretics, and particlemorphology.

The therapeutically effective amount of the calcium receptor-activecompound in the compositions disclosed herein ranges from about 1 mg toabout 360 mg, for example from about 5 mg to about 240 mg, or from about20 mg to about 100 mg. As used herein, the “therapeutically effectiveamount” is an amount that changes in a desired manner at least one ofthe calcium level, the phosphorus level, the PTH level, and the calciumphosphorus product in a subject. In some embodiments, thetherapeutically effective amount of cinacalcet HCl in the compositiondisclosed herein can be chosen from about 5 mg, about 15 mg, about 30mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg,about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 300 mg, orabout 360 mg.

While it may be possible to administer a compound of the inventionalone, the compound administered will normally be present as an activeingredient in a pharmaceutical composition. Thus, a pharmaceuticalcomposition of the invention may comprise a therapeutically effectiveamount of at least one calcium receptor-active compound, or an effectivedosage amount of at least one calcium receptor-active compound.

As used herein, an “effective dosage amount” is an amount that providesa therapeutically effective amount of the at least one calcium receptoractive compound when provided as a single dose, in multiple doses, or asa partial dose. Thus, an effective dosage amount of the at least onecalcium receptor active compound of the invention includes an amountless than, equal to or greater than an effective amount of the compound;for example, a pharmaceutical composition in which two or more unitdosages, such as in tablets, capsules and the like, are required toadminister an effective amount of the compound, or alternatively, amultidose pharmaceutical composition, such as powders, liquids and thelike, in which an effective amount of the at least one calciumreceptor-active compound is administered by administering a portion ofthe composition.

Alternatively, a pharmaceutical composition in which two or more unitdosages, such as in tablets, capsules and the like, are required toadminister an effective amount of the at least one calcium receptoractive compound may be administered in less than an effective amount forone or more periods of time (i.e., a once-a-day administration, and atwice-a-day administration), for example to ascertain the effective dosefor an individual subject, to desensitize an individual subject topotential side effects, to permit effective dosing readjustment ordepletion of one or more other therapeutics administered to anindividual subject, and/or the like.

The effective dosage amount of the pharmaceutical composition disclosedherein ranges from about 1 mg to about 360 mg from a unit dosage form,for example about 5 mg, about 15 mg, about 30 mg, about 50 mg, about 60mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg,about 210 mg, about 240 mg, about 300 mg, or about 360 mg from a unitdosage form.

In some embodiments of the present invention, the compositions disclosedherein comprise a therapeutically effective amount of cinacalcet HCl forthe treatment of hyperparathyroidism, such as primaryhyperparathyroidism and secondary hyperparathyroidism, hyperphosphonia,hypercalcemia, and elevated calcium-phosphorus product. For example, incertain embodiments, the cinacalcet HCl can be present in an amountranging from about 1% to about 70%, such as from about 5% to about 40%,from about 10% to about 30%, or from about 15% to about 20%, by weightrelative to the total weight of the composition.

The compositions of the invention may contain one or more activeingredients in addition to the calcium receptor-active compound. Theadditional active ingredient may be another calcium receptor-activecompound, or it may be an active ingredient having a differenttherapeutic activity. Examples of such additional active ingredientsinclude, for example, vitamins and their analogs, such as vitamin D andanalogs thereof, antibiotics, and cardiovascular agents.

The cinacalcet HCl or other calcium receptor-active compound that can beused in the composition is typically present in the form of particles.These particles can have a particle D₅₀ of, for example, less than orequal to about 50 μm. As used herein, the “particle D₅₀” is the particlesize of the active pharmaceutical ingredient at the 50^(th) percentileof a particle size distribution. According to certain embodiments of theinvention, the active pharmaceutical ingredient in the formulation has aparticle D₅₀ that is less than the granule D₅₀ of the formulation,discussed in detail below.

The particle D₅₀ of the cinacalcet HCl particles can be determined byone of ordinary skill in the art using known light scatteringtechniques. In one embodiment of the invention, the particle D₅₀ of thecinacalcet HCl particles is determined by using a particle sizeanalyzer, such as a Malvern Mastersizer analyzer, that uses a laser toscan a suspension of particles. The particles diffract the incominglight to detectors: smaller particles diffract light at larger angles,while larger particles diffract light at smaller angles. The lightintensities observed at each detector are translated into a particlesize distribution based on the diameter of a sphere that has anequivalent volume to that of the measured particles.

Specifically, the particle size distribution of the activepharmaceutical ingredient, for example, cinacalcet HCl, can bedetermined according to the following procedure. The followinginstrument conditions in a Malvern Mastersizer particle size analyzerare specified in its software:

Refractive Index Sample 1.630 Absorptive Index 0.1 Refractive IndexDispersant 1.375 Analysis model General purpose spherical Calculationsensitivity Enhanced Measurement snaps and 20,000 snaps over 20 secondstime Background snaps and time 20,000 snaps over 20 seconds Stir speed1750 rpm

While stirring, about 170 mL of a dispersion of about 0.1% sorbitantrioleate (for example Span 85®, available from Kishida Chemical) inhexane (“dispersant-B”), is added to the sampling unit, and the laser isaligned to take a background measurement of the dispersant-B.

The entire suspension containing the cinacalcet HCl is added until asuitable obscuration range ranging from about 10 to about 20% isobtained. The sample is measured after the obscuration value hasstabilized. After the measurement, the system is drained and rinsed oncewith about 170 mL of dispersant-B, the dispersant-B is drained, and thesampling unit is refilled with about 170 mL of dispersant-B. Themeasurement are repeated two more times with different riffledfractions. The riffling is performed on large samples to obtain smallrepresentative particle size fractions about 15 mg in size.

The Obscuration, D(v,0.1), D(v,0.5), D(v,0.9) values are then calculatedfrom these measurements. The average, standard deviation, and relativestandard deviation (RSD) of the D(v,0.1), D(v,0.5), D(v,0.9) values isalso calculated. The RSD (%) is calculated as follows:

${{RSD}\mspace{14mu}(\%)} = {\frac{100}{X}\left\lbrack \frac{\sum\limits_{i = 1}^{N}\;\left( {X_{i} - \overset{\_}{X}} \right)^{2}}{N - 1} \right\rbrack}^{\frac{1}{2}}$

where X, is an individual measurement in a set of N measurements and isthe arithmetic mean of the set.

The composition disclosed herein can be in various forms, for example,in granular form. The granules that can be used in the present inventioncan have a granule D₅₀ ranging from about 50 μm to about 150 μm, such asfrom about 80 μm to about 130 μm. As defined herein, the “granule D₅₀”is the particle size of the composition at the 50^(th) percentile of aparticle size distribution. The granule D₅₀ can readily be determined byone of ordinary skill in the art using sieve analysis techniques.Specifically, the granule D₅₀ is determined according to the followingprocedure.

Approximately 100 g of sample is added to sieve shaker equipped with 40mesh, 60 mesh, 80 mesh, 100 mesh, 140 mesh, 200 mesh, 325 mesh, and thebottom pan. The sieve shaker is then turned on for about 10 minutes toseparate the sample according to particle size. Each sieve is weighed todetermine the amount of sample retained on each sieve and the bottompan. The individual sieve weight is normalized to generate sieve weightfraction. The individual sieve weight fraction is calculated by dividingeach sieve weight with the sum of all sieve weights.

${{Weight}\mspace{14mu}{Fraction}\mspace{14mu}{of}\mspace{14mu}{each}\mspace{14mu}{sieve}} = \frac{{Weight}\mspace{14mu}{of}\mspace{14mu}{each}\mspace{14mu}{sieve}}{{Sum}\mspace{14mu}{of}\mspace{14mu}{all}\mspace{14mu}{sieves}}$

Before the particle size calculation, the mean size range must bedetermined for each sieve and the bottom pan. This mean size of eachsieve screen represents the mean particle size retained on the screen.The mean size of each sieve screen is determined by the hole size of thescreen (lower limit) and one sieve size larger (upper limit). In thecase of the 40 mesh sieve screen, the hole size of about 1410 μm is usedas an upper limit. Table 1 set forth below shows the particle size rangeof any retained material on each screen and the mean of the particlesize range.

TABLE 1 Particle size range of retained Median Hole size of materialparticle each screen on each screen size of the Screens (μm) (μm) screen(μm)  40 mesh 425  425-1410 918  60 mesh 250 250-424 337  80 mesh 180180-249 215 100 mesh 150 150-179 165 140 mesh 106 106-149 128 200 mesh75  75-105 90 325 mesh 45 45-74 60 Bottom pan 0  1-44 23

The weight fraction of each sieve is added to generate cumulativefrequency distribution starting from the bottom pan to 40 mesh screen.Once the cumulative frequency distribution is generated, thecorresponding particle size at 10 percentile (D₁₀), 50-percentile (D₅₀),and 90-percentile (D₉₀) are determined. The particle size of thecorresponding percentile is determined by linear interpolation betweentwo consecutive data from the cumulative frequency distribution. Forexample, particle size of 50-percentile (D₅₀) is interpolated by,

${D_{50}({\mu m})} = \frac{\left\lbrack {{\left( {50 - X_{n}} \right)*d_{n + 1}} + {\left( {X_{n + 1} - 50} \right)*d_{n}}} \right\rbrack}{\left( {X_{n + 1} - X_{n}} \right)}$

where,

X_(n)=cumulative quantity of sample that is just below 50-percentile (in%);

d_(n)=mean of the particle size range from the sieve screen where X_(n)occurs (in mm);

X_(n+1)=next cumulative quantity of sample that is above 50-percentile(in %).

d_(n+1)=mean of the particle size range from the sieve screen whereX_(n+1) occurs (in mm).

According to all embodiments of the present invention, the particle sizeof active pharmaceutical ingredient is measured according to lightscattering techniques, and the particle size of the granules ofcomposition is measured according to sieve analysis.

The compositions disclosed herein can be in a form chosen from, forexample, tablets, capsules, and powders. The tablets can be made bypressing the granules into the form of tablets. The capsules can also bemade using the granules.

The at least one pharmaceutically acceptable excipient can be chosenfrom, for example, diluents such as starch, microcrystalline cellulose,dicalcium phosphate, lactose, sorbitol, mannitol, sucrose, methyldextrins; binders such as povidone, hydroxypropyl methylcellulose,dihydroxy propylcellulose, and sodium carboxyl methylcellulose; anddisintegrants such as crospovidone, sodium starch glycolate,croscarmellose sodium, and mixtures of any of the foregoing. The atleast one pharmaceutically acceptable excipient can further be chosenfrom lubricants such as magnesium stearate, calcium stearate, stearicacid, glyceryl behenate, hygrogenated vegetable oil, glycerine fumarateand glidants such as colloidal silicon dioxide, and mixtures thereof. Insome embodiments of the present invention, the at least onepharmaceutically acceptable excipient is chosen from microcrystallinecellulose, starch, talc, povidone, crospovidone, magnesium stearate,colloidal silicon dioxide, sodium dodecyl sulfate, and mixtures of anyof the foregoing. The excipients of the present invention, can beintragranular, intergranular, or mixtures thereof.

In some embodiments of the present invention, the composition and/or thegranules within the composition can comprise microcrystalline celluloseand starch in a weight ratio ranging from about 1:1 to about 15:1. Forexample, in the composition, the weight ratio of the microcrystallinecellulose and starch can range from about 1:1 to about 15:1, such asabout 10:1, and in the granules within the composition, the weight ratioof the microcrystalline cellulose and starch can range from about 1:1 toabout 10:1, such as about 5:1.

The microcrystalline cellulose can be present in an amount ranging fromabout 25% to about 85%, for example from about 50% to about 80%, or fromabout 60% to about 75% by weight relative to the total weight of thecomposition. The starch can be present in an amount ranging from about5% to about 35%, for example, from about 5% to about 25%, or from about5% to about 10% by weight relative to the total weight of thecomposition.

The compositions disclosed herein can further comprise at least oneingredient chosen from coating materials that are known in the art suchas, for example, hydroxypropyl methylcellulose.

Certain compositions can comprise:

(a) from about 10% to about 40% by weight of a calcium receptor-activecompound chosen from cinacalcet HCl and cinacalcet methanesulfonate;

(b) from about 45% to about 85% by weight of at least one diluent;

(c) from about 1% to about 5% by weight of at least one binder; and

(d) from about 1% to about 10% by weight of at least one disintegrant;

wherein the percentage by weight is relative to the total weight of thecomposition. The compositions can further comprise from about 0.05% toabout 5% by weight, relative to the total weight of the composition, ofat least one additive chosen from glidants, lubricants, and adherents.The composition can additionally comprise from about 1% to about 6% byweight of at least one coating material, relative to the total weight ofthe composition.

In another embodiment, the composition disclosed herein comprises:

(a) from about 10% to about 40% by weight of cinacalcet HCl;

(b) from about 5% to about 10% by weight of starch;

(c) from about 40% to about 75% by weight of microcrystalline cellulose;

(d) from about 1% to about 5% by weight of povidone; and

(e) from about 1% to about 10% by weight of crospovidone;

wherein the percentage by weight is relative to the total weight of thecomposition.

The povidone can be present in an amount ranging from about 1% to about5%, for example, from about 1% to about 3% by weight relative to thetotal weight of the composition. The crospovidone can be present in anamount ranging from about 1% to about 10%, for example from about 3% toabout 6%, by weight relative to the total weight of the composition.

The composition can further comprise from about 0.05% to about 5% byweight, relative to the total weight of the composition, of at least oneadditive chosen from colloidal silicon dioxide, magnesium stearate,talc, and the like, and mixtures of any of the foregoing. In certainembodiments of the invention, the composition comprises from about 0.05%to about 1.5% of colloidal silicon dioxide, from about 0.05% to about1.5% of magnesium stearate, from about 0.05% to about 1.5% of talc, ormixtures of any of the foregoing. The composition can even furthercomprise from about 1% to about 6% by weight of at least one coatingmaterial, relative to the total weight of the composition.

As mentioned above, the compositions of certain embodiments of thepresent invention have a dissolution profile that results in about 50%to about 125% of a target amount of the calcium receptor-active compoundbeing released from the composition no later that about 30 minutes fromthe start of a dissolution test that is conducted in 0.05 N HCl in aU.S.P. 2 apparatus at a temperature of 37° C.±0.5° C. at a rotationspeed of 75 r.p.m. The dissolution test is conducted using a USP 2apparatus, and according to the dissolution protocol described in USP26/NF 21, chapter 711, which is incorporated herein by reference.According to this embodiment using this dissolution protocol, a statedvolume of the dissolution medium (±1%) is placed in the vessel of theUSP 2 apparatus, the apparatus is assembled, the dissolution medium isequilibrated to 37° C.±0.5° C., the thermometer is removed, the dosageform is placed in the vessel, and the amount of active pharmaceuticalingredient that is released as a function of time is measured.

According to another embodiment of the invention, a stated volume of thedissolution medium is placed in the vessel of the USP 2 apparatus, theapparatus is assembled, the dissolution medium is equilibrated to about37° C., the thermometer is removed, the dosage form is placed in thevessel, and the amount of active pharmaceutical ingredient that isreleased as a function of time is measured.

The dissolution profile represents the percentage of the activepharmaceutical ingredient released based on a target amount of theactive pharmaceutical ingredient in the formulation. As used herein“target amount” refers to the amount of active pharmaceutical ingredientin each formulation. In certain embodiments, the target amount refers tothe label amount and/or label claim.

USP 26/NF 21, chapter 905, defines a protocol used to determine thedosage-unit conformity according to the present invention, and thiscontent uniformity protocol is incorporated herein by reference.According to this protocol, the content uniformity is determined bymeasuring the amount of active pharmaceutical ingredient in 10 dosageunit samples, and calculating whether the amount of activepharmaceutical ingredient in all the dosage unit samples falls within arange of 85% to 115% of the target amount. If one dosage unit sample isoutside the range of 85% to 115% of the target amount and no unit isoutside a range of 75% to 125% of the target amount, or if the RelativeStandard Deviation (RSD), which is the sample standard deviationexpressed as a percentage of the mean, is not greater than 6%, then 20additional dosage unit samples are tested. After treating at least 30dosage units, the content uniformity requirement is met if not more thanone dosage unit sample is outside the range of 85% to 115% of the targetamount, and no unit is outside a range of 75% to 125% of the targetamount, and the RSD of the at least 30 dosage units does not exceed7.8%.

In certain embodiments, the dissolution profile of the compositionsdisclosed herein can result in, for example, at least about 50%, atleast about 70%, at least about 75%, or at least about 85%, of thetarget amount of the calcium receptor-active compound being releasedfrom the composition no later than about 30 minutes from the start ofthe test. In certain embodiments, the dissolution profile of thecompositions disclosed herein can comprise at most about 125%, forexample at most about 115%, at most about 110%, or at most about 100% ofthe target amount of the calcium receptor-active compound being releasedfrom the composition no later than about 30 minutes from the start ofthe test. In additional embodiments, the dissolution profile of thecompositions disclosed herein can comprise from about 50% to about 125%,for example from about 70% to about 110%, of the target amount of thecalcium receptor-active compound being released from the composition nolater than about 30 minutes from the start of the test.

Other embodiments of the present invention are directed to a method ofmaking a pharmaceutical composition comprising:

(a) forming a granule comprising a calcium receptor-active compound andat least one pharmaceutically acceptable excipient as disclosed herein;and

(b) controlling the particle size of the granule such that from about50% to about 125% of a target amount of calcium receptor-active compoundis released from the composition no later than about 30 minutes from thestart of a test in 0.05 N HCl according to a dissolution test conductedin a USP 2 apparatus at a temperature of 37° C.±0.5° C., and a rotationspeed of 75 r.p.m.

Further embodiments of the present invention are directed to a method ofmaking a pharmaceutical composition comprising:

(b) forming a granule comprising a calcium receptor-active compound andat least one pharmaceutically acceptable excipient as disclosed herein;and

(b) controlling the particle size of the granule such that from about50% to about 125% of a target amount of calcium receptor-active compoundis released from the composition no later than about 30 minutes from thestart of a test in 0.05 N HCl according to a dissolution test conductedin a USP 2 apparatus at a temperature of about 37° C., and a rotationspeed of about 75 r.p.m.

The granule can be formed by any known process, such as high wet sheargranulation, low wet shear granulation, fluid bed granulation, rotarygranulation, extrusion-spheronization, dry granulation, rollercompaction, and the like.

The particle size of the granule of the composition can be controlled byvarious factors. In certain embodiments of the present invention, theparticle size of the granule of the composition can be controlled by theamount of water added to the materials present in a granulator. Forexample, a desired particle size of the granule can be achieved when thegranulator has a volume ranging from about 1 L to about 1200 L, such asfrom about 65 L to about 1200 L, or from about 300 L to about 800 L, andthe amount of water added ranges from about 20% to about 40%, such asfrom about 30% to about 36%, relative to the amount of dry powderspresent in the granulator to form the granules.

The granulator's impeller tip speed can also affect the particle size ofthe granules. In some embodiments, the impeller tip speed, measured inmeters per second (m/s), can range from about 5 m/s to about 10 m/s,such as from about 7 m/s to about 9 m/s.

Other embodiments of the present invention are directed to a method ofmaking a pharmaceutical composition comprising

(a) forming a composition comprising a therapeutically effective amountof particles of a calcium receptor-active compound and at least onepharmaceutically acceptable excipient as disclosed herein; and

(b) controlling the particle size of the calcium receptor-activecompound such that from about 50% to about 125% of a target amount ofthe calcium receptor-active compound is released from the composition nolater than about 30 minutes from the start of a test in 0.05 N HClaccording to a dissolution test conducted in a USP 2 apparatus at atemperature of 37° C.±0.5° C., and a rotation speed of 75 r.p.m.

Additional embodiments of the present invention are directed to a methodof making a pharmaceutical composition comprising

(a) forming a composition comprising a therapeutically effective amountof particles of a calcium receptor-active compound and at least onepharmaceutically acceptable excipient as disclosed herein; and

(b) controlling the particle size of the calcium receptor-activecompound such that from about 50% to about 125% of a target amount ofthe calcium receptor-active compound is released from the composition nolater than about 30 minutes from the start of a test in 0.05 N HClaccording to a dissolution test conducted in a USP 2 apparatus at atemperature of about 37° C., and a rotation speed of about 75 r.p.m.

The size of the particles is controlled during the production of theactive pharmaceutical ingredient, for example, by use of a milling step,or a controlled crystallization process. For example, the activepharmaceutical ingredient can be milled using a stainless steel hammermill with 5 mm screen and 12 hammers forward at a mill speed of 8100±100rpm, with the feed speed is set at 90±10 rpm.

Yet other embodiments of the present invention are directed to a methodfor the treatment of a disease or disorder that can be treated byaltering a subject's calcium receptor activity. In some embodiments, amethod for the treatment of a disease chosen from hyperparathyroidism,such as primary hyperparathyroidism and secondary hyperparathyroidism,hyperphosphonia, hypercalcemia, and elevated calcium-phosphorus productcomprises administering to a patient, such as human, an effective dosageamount of a pharmaceutical composition comprising a calciumreceptor-active compound and at least one pharmaceutically acceptableexcipient as disclosed herein, wherein the composition has a dissolutionprofile in 0.05 N HCl, measured according to a dissolution testconducted in a USP 2 apparatus at a temperature of 37° C.±0.5° C., andat a rotation speed of 75 r.p.m., which comprises from about 50% toabout 125% of a target amount of the calcium receptor-active compoundbeing released from the composition in no later than about 30 minutesfrom the start of the test.

A further embodiment of the present invention is directed to a methodfor the treatment of a disease chosen from hyperparathyroidism,hyperphosphonia, hypercalcemia, and elevated calcium-phosphorus productcomprises administering to a patient, such as human, an effective dosageamount of a pharmaceutical composition comprising a calciumreceptor-active compound and at least one pharmaceutically acceptableexcipient as disclosed herein, wherein the composition has a dissolutionprofile in 0.05 N HCl, measured according to a dissolution testconducted in a USP 2 apparatus at a temperature of about 37° C., and ata rotation speed of about 75 r.p.m., which comprises from about 50% toabout 125% of a target amount of the calcium receptor-active compoundbeing released from the composition in no later than about 30 minutesfrom the start of the test.

Reference will now be made to the following examples which are notintended to limit the invention. To the contrary, it will be appreciatedthat various alternatives, modifications, and equivalents may beincluded within the spirit and scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: A process Flow diagram showing a process by which 30-, 60- and90-mg tablets of active pharmaceutical ingredient are prepared.

EXAMPLES

Three pharmaceutical formulations with target amounts of 30 mg, 60 mg,and 90 mg active pharmaceutical ingredient with the following componentswere prepared:

30 mg 60 mg 90 mg Weight Tablet Tablet Tablet % Amount Amount Amount(w/w) (mg) (mg) (mg) Cinacalcet HCl 18.367 33.06 66.12 99.18Pregelatinized starch (Starch 33.378 60.08 120.16 180.24 1500)Microcrystalline cellulose 6.678 12.02 24.04 36.06 (Avicel PH102)Povidone (Plasdone K29/32) 2.044 3.68 7.36 11.04 Crospovidone(Polyplasdone 1.233 2.22 4.44 6.66 XL) Purified Water¹ — — — —Microcrystalline cellulose 34.300 61.74 123.48 185.22 (Avicel PH102)Magnesium stearate 0.500 0.90 1.80 2.70 Colloidal silicon dioxide 0.5000.90 1.80 2.70 (Colloidal anhydrous silica) (Cab-O-Sil M5P) Crospovidone(Polyplasdone 3.000 5.40 10.80 16.20 XL) Core Tablet 100.000 180.00360.00 540.00 Purified Water¹ — — — — Opadry ® II (colored film former)4.000 7.20 14.40 21.60 Purified Water¹ — — — — Opadry ® Clear (clearfilm 1.500 2.70 5.40 8.10 former) Carnauba Wax Powder 0.010 0.018 0.0360.054 Opacode ® Ink (Black)² — — — — 1 ¹The purified Water was removedduring processing. ²Trace quantities of ink were applied to the coatedtablet.

The wet granulation process was conducted in a PMA 800 L high-sheargranulator with water serving as the granulation fluid. The cinacalcetHCl and the intra-granulation excipients (pregelatinized starch,microcrystalline cellulose, povidone, and crospovidone) were dry-mixedfor 1 to 2 minutes with an impeller speed set point at 116±10 rpm,followed by granulation with 30.0% to 36.0% w/w water (based onintra-granular lot size; target was 34.9% w/w) with an impeller speedset point at 116±10 rpm and at a slow or fast chopper speed (target wasslow speed). During the granulation process water was delivered at9.8±0.5 kg/min.

Following granulation, the mixture was wet-milled using an in-line Comilequipped with a 0.375″ (0.953 cm) opening screen and an impeller speedset point at 1400±50 rpm. The mixture was then discharged into afluid-bed dryer.

After completion of the wet-milling process, the granulation mixture wasdried in an Aeromatic MP6 fluid bed dryer with an inlet temperature setpoint at 70°±5° C. When the outlet temperature reached 37° C. to 41° C.,samples were taken to determine moisture levels by loss on drying (LOD).The granules were dried until the average moisture levels reached 1.0%to 2.5%.

The dried granulation mixture was milled through a Quadro Mill 196S(Comil) equipped with a 0.055″ (0.140 cm) opening screen at an impellerspeed of 1650±50 rpm into a 1000 L Gallay tote.

Except for magnesium stearate, the extra-granular excipients wereblended in a 650 L Gallay tote blender for 7±1 minutes at 12±1 rpm. Thismixture was further blended with the dry-milled granulation in a 1000 LGallay tote blender for 15±5 minutes at 12±1 rpm, and then for 6±1minutes at 12±1 rpm after magnesium stearate was added for lubrication.

The final lubricated blend was compressed into tablets containing 30-,60-, or 90 mg of the free base equivalent of active cinacalcet HCl usinga Unipress 27 tablet press set to a speed of 2000±300 tablets per minuteand equipped with a force feeder. Throughout the compression operation,individual tablet weights (target weights of 180, 360, and 540 mg for30-, 60-, and 90-mg tablets, respectively), the average weight of 10tablets, tablet hardness and thickness were monitored at pre-determinedintervals.

The color-coating suspension and clear-coating solution were prepared byslowly adding either the Opadry® II (green) or Opadry® Clear intopurified water while mixing until uniform (≧45 minutes). The colorsuspension and clear solution deaerated for ≧45 minutes before thespraying process began, and were used within a pre-determined timelimit.

Each lot was film-coated with color and clear coats in a VectorHi-Coater 48″ pan. The color-coating suspension was applied onto amoving core tablet bed (pan speed=4 to 7 rpm) and a spray rate of 250±50grams per minute per 3 guns. The distance between the spray guns and thetablet bed was approximately 8″ (20 cm) to 11″ (28 cm), and the airvolume was 600±200 ft³ per minute (17.1±5.7 m³ per minute) with a panpressure differential maintained between −0.1″ (−0.25 cm) to −0.3″(−0.76 cm) of water. Supply air temperature was adjusted to 80±10° C. tomaintain an exhaust temperature of 41±3° C.

When the clear-coating application was completed, the heater and the airsupply was turned off and the wax was spread evenly over the movingtablet bed (after it reached ≦37° C.) with a pan speed of 4 to 7 rpm.The tablets were rotated for 5±1 minutes, and after the supply air andexhaust fan were turned on, the tablets were rotated for an additional5±1 minutes with a pan speed of 4 to 7 rpm and supply air of 600±200 ft³per minute (17.1±5.7 m³ per minute). The pan was jogged until the tabletbed temperature reached ≦30° C.

An Ackley ink-based offset printer was used to produce 2-sided printedtablets.

The dissolution profile of the three formulations were measuredaccording the dissolution protocol described in the USP 26/NF 21,chapter 711 using a USP 2 apparatus at a temperature of about 37° C.,and at a rotation speed of about 75 r.p.m. The dissolution profile ofthe formulations in which at least about 75% of the cinacalcet HCl wasreleased from the composition in no later than about 30 minutes from thestart of the test is set forth in Table 2.

TABLE 2 Time (min) 30 mg Tablet 60 mg Tablet 90 mg Tablet 15 85.3 81.980.8 30 95.2 93.8 93.4 45 97.7 97.7 97.9 60 98.7 98.8 99.8

The content uniformity of the three formulations were measured inaccordance with USP 26/NF 21, chapter 905, described in detail above.The content uniformity and for each of the three formulations is setforth in Table 3.

TABLE 3 30 mg Tablet 60 mg Tablet 90 mg Tablet Mean Mean Mean (10 (10(10 Container tablets) % RSD tablets) % RSD tablets) % RSD  1 (beg.)98.5 0.8 96.7 1.6 99.7 1.2  5 98.8 0.8 98.5 0.8 100.7 0.9 11 98.5 0.698.3 1.0 99.9 0.7 16 98.3 0.8 97.6 1.3 99.9 0.5 22 98.3 1.0 96.3 1.8100.7 0.9 end 98.0 0.6 95.8 1.9 99.3 0.8

What is claimed is:
 1. A pharmaceutical composition comprising: (a) fromabout 10% to about 40% by weight of cinacalcet HCl in an amount of fromabout 20 mg to about 100 mg; (b) from about 45% to about 85% by weightof a diluent selected from the group consisting of microcrystallinecellulose, starch, dicalcium phosphate, lactose, sorbitol, mannitol,sucrose, methyl dextrins, and mixtures thereof, (c) from about 1% toabout 5% by weight of at least one binder selected from the groupconsisting of povidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and mixtures thereof; and (d)from about 1% to 10% by weight of at least one disintegrant selectedfrom the group consisting of crospovidine, sodium starch glycolate,croscarmellose sodium, and mixtures thereof, wherein the percentage byweight is relative to the total weight of the composition, and whereinthe composition is for the treatment of at least one ofhyperparathyroidism, hyperphosphonia, hypercalcemia, and elevatedcalcium phosphorus product.
 2. The composition according to claim 1,further comprising at least one excipient selected from the groupconsisting of lubricants and clear and color coating materials.
 3. Thecomposition according to claim 1, further comprising from about 1% toabout 6% by weight of at least one coating material selected from thegroup consisting of clear and color coating materials wherein thepercentage by weight is relative to the total weight of the composition.4. The composition according to claim 1, further comprising from about0.05% to about 5% of at least one additive selected from the groupconsisting of glidants, lubricants and adherents, wherein the percentageby weight is relative to the total weight of the composition.
 5. Thecomposition according to claim 1, wherein the at least one binder ispovidone.
 6. The composition according to claim 1, wherein the at leastone disintegrant is crospovidone.
 7. The composition according to claim6 wherein the form of the cinacalcet HCl is selected from the groupconsisting of needle-shape particles, rod-shape particles, plate-shapedparticles, and mixtures thereof.
 8. The composition according to claim1, wherein the cinacalcet HCl is in a form selected from the groupconsisting of amorphous powders, crystalline particles, and mixturesthereof.
 9. The composition according to claim 8 wherein the particleD₅₀ of the cinacalcet HCl particles is less than or equal to about 50μm.
 10. The composition according to claim 9, wherein the granules havea granule D₅₀ measured using a sieve analysis ranging from about 50 μmto about 150 μm.
 11. The composition according to claim 9, wherein thegranules have a granule D₅₀ measured using a sieve analysis ranging fromabout 80 μm to about 130 μm.
 12. The composition according to claim 11,wherein the crospovidone is present intergranularly.
 13. The compositionaccording to claim 11, wherein the crospovidone is presentintragranularly.
 14. The composition according to claim 9, wherein thedisintegrant is crospovidone and the crospovidone is presentintergranularly, intragranularly, or a combination thereof.
 15. Thecomposition according to claim 1 wherein the composition comprisesgranules.
 16. The composition according to claim 1 further comprisingfrom about 0.05% to about 1.5% by weight of colloidal silicon dioxiderelative to the total weight of the composition.
 17. The compositionaccording to claim 1 further comprising from about 0.05% to about 1.5%by weight of magnesium stearate relative to the total weight of thecomposition.
 18. The composition according to claim 1, wherein thehyperparathyroidism is primary hyperparathyroidism or secondaryhyperparathyroidism.
 19. The composition according to claim 1, whereinthe diluent is microcrystalline cellulose or starch.
 20. Apharmaceutical composition comprising: (a) from about 10% to about 40%by weight of cinacalcet HCl in an amount of from about 20 mg to about100 mg; (b) from about 45% to about 85% by weight of a diluent selectedfrom the group consisting of microcrystalline cellulose, starch,dicalcium phosphate, lactose, sorbitol, mannitol, sucrose, methyldextrins, and mixtures thereof, (c) from about 1% to about 5% by weightof at least one binder selected from the group consisting of povidone,hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodiumcarboxymethylcellulose, and mixtures thereof; and (d) from about 1% to10% by weight of at least one disintegrant selected from the groupconsisting of crospovidine, sodium starch glycolate, croscarmellosesodium, and mixtures thereof, wherein the disintegrant is at leastpresent intragranularly and wherein the composition is for the treatmentof at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia,and elevated calcium phosphorus product.
 21. A pharmaceuticalcomposition comprising: (a) from about 10% to about 40% by weight ofcinacalcet HCl in an amount of from about 20 mg to about 100 mg; (b)from about 5% to about 10% by weight of starch; (b) from about 40% toabout 75% by weight of microcrystalline cellulose, (c) from about 1% toabout 5% by weight of povidone, and (d) from about 1% to 10% by weightof crospovidone, wherein the percentage by weight is relative to thetotal weight of the composition, and wherein the composition is for thetreatment of at least one of hyperparathyroidism, hyperphosphonia,hypercalcemia, and elevated calcium phosphorus product.
 22. Thecomposition according to claim 21 further comprising from about 0.05% toabout 1.5% by weight of colloidal silicon dioxide relative to the totalweight of the composition.
 23. The composition according to claim 21further comprising from about 0.05% to about 1.5% by weight of magnesiumstearate relative to the total weight of the composition.